Esters y-hydroxy-a.P-unsaturated

Stork and Kahn- have reported similar highly stereoselective OsOj-catalyzed hydrox-ylation of the y-hydroxy a,P-unsaturated esters 1 and 3. The corresponding acids exhibit lower stereoselectivity. 

Maier and Varseev recently applied MacMillan s elegant one-pot three-step protocol 115) (1. a-hydroxylation, 2. Horner-Wadsworth-Emmons HWE) olefination, 3. N—O cleavage) for the conversion of the (5)-citronellol-derived aldehyde 132 to y-hydroxy-a,p-unsaturated ester 133 early in their 18-step first total synthesis of neosymbioimine (134) 116), a minor amphoteric metabolite of the symbiotic marine dinofiagellate Symbiodinium sp. 117) (Scheme 31). 

Scheme 3.12 Kinetic resolution of y-hydroxy-a.P-unsaturated esters...

Scheme 7.70 Proposed mechanism for the multi-step one-pot synthesis of y-alkoxy or y-hydroxy a,p-unsaturated esters and nitriles...

A route to ( , )-2,4-alkadienoic esters involves the Johnson-Claisen rearrangement of y-hydroxy-a,P-unsaturated sulfones and subsequent elimination of PhSO H with DBU. Stereoselective access to trisubstituted enol ethers initiated by iodoalkoxylation of disubstituted alkenes (with PyjIBF, 2HBF, ROH) is concluded by treatment with DBU.5... 

Alkylative esterification of carboxylic acids with alkyl halides are effected by action with TMG (1) [65]. An ester is given by the TMG (1) mediated reaction of y-hydroxy-a,p-unsaturated carboxylic acid with methyl iodide without lactone formation after isomerization [65a]. Barton s base effectively works in the alkylation of sterically hindered carboxylic acid [3]. Ethanolysis of the acetate of tertiary alcohol occurred easily in 86% yield in the presence of BTMG (2) [66] (Scheme 4.24). 

However, most asymmetric 1,3-dipolar cycloaddition reactions of nitrile oxides with alkenes are carried out without Lewis acids as catalysts using either chiral alkenes or chiral auxiliary compounds (with achiral alkenes). Diverse chiral alkenes are in use, such as camphor-derived chiral N-acryloylhydrazide (195), C2-symmetric l,3-diacryloyl-2,2-dimethyl-4,5-diphenylimidazolidine, chiral 3-acryloyl-2,2-dimethyl-4-phenyloxazolidine (196, 197), sugar-based ethenyl ethers (198), acrylic esters (199, 200), C-bonded vinyl-substituted sugar (201), chirally modified vinylboronic ester derived from D-( + )-mannitol (202), (l/ )-menthyl vinyl ether (203), chiral derivatives of vinylacetic acid (204), ( )-l-ethoxy-3-fluoroalkyl-3-hydroxy-4-(4-methylphenylsulfinyl)but-1 -enes (205), enantiopure Y-oxygenated-a,P-unsaturated phenyl sulfones (206), chiral (a-oxyallyl)silanes (207), and (S )-but-3-ene-1,2-diol derivatives (208). As a chiral auxiliary, diisopropyl (i ,i )-tartrate (209, 210) has been very popular. 

An important application of the Reformatsky reaction is the conversion of P-hydroxy esters to a, P-unsaturated esters. Acid-catalyzed dehydration usually leads to a mixture of a, P- and P, y-unsaturated esters. However, conversion of the initially formed p-hydroxy esters to their corresponding acetates by treatment with acetyl chloride, followed by base-catalyzed dehydration with NaOEt, produces conjugated esters in high purity. This sequence of reactions provides an alternative route to the Homer-Wads worth-Emmons olefmation of ketones (see Chapter 8). 

This new method for the construction of a-hydroxy-y-lactones is quite general for a variety of alcohols and a,P-unsaturated esters (Figure 6.9). The preparation of a-hydroxy-y-spirolactones from cyclic alcohols is especially notable, because these spirolactones have been very difficult to synthesize until now. The reaction can be explained by Scheme 6.18 (i) in situ generation of an a-hydroxy carbon radical from an alcohol assisted by NHPI/Co(II)/02, (ii) the addition of the radical to methyl acrylate, (iii) trapping of the adduct radical by O2, and (iv) intramolecular cydization to give a-hydroxy-y-butyrolactone. Considering the low-cost material, reaction efficiency, and reaction simplicity, this method provides an innovative approach to a-hydroxy-y-lactones which has considerable industrial potential. 

T. Iwahama, S. Sakaguchi, Y. Ishii, Catalytic a-hydroxy carbon radical generation and addition. Synthesis of a-hydroxy-y-lactones from alcohols, a,p-unsaturated esters and dioxygen, Chem. Commun. (2000) 613-614. 

In 1993, Tiecco et al. reported a similar reaction for p,y-unsaturated esters, amides or nitriles with 10 mol% of diphenyl diselenide (449) and an excess of ammonium persulfate in alcohols or water to afford the y-alkoxy or y-hydroxy a,ji-unsaturated derivatives in good yields (Table 7.32) [311],... 

The 9,10-phosphonostearic acid in form of its sodium salt shows a good thermal stability and was efficient as an inhibitor in rust protection. The diethyl-phosphonoacetoxystearic acid methyl ester is used as additive in high-pressure lubricants. Rust protection properties are also shown by 9,10-phosphonostearyl alcohol [157]. Trisodium 9,10-phosphonostearate possesses the best surface activity in an 0.2% aqueous solution showing 33 mN/m at 30°C and a pH value of 10.5 [156]. By the addition of dialkyl phosphite to a,p-unsaturated ketones the y-oxophosphonic acids are available [159]. Addition of dialkyl phosphite to y-ketoacids leads to a-hydroxy-y-carboxyphosphonates see Eq. (86) ... 

The unified highly convergent total and formal syntheses of ( + )-macro-sphelides B (441 X = O) and A (441 X = a-OH, p-H), respectively, have been described (483). Key features of the syntheses include the concise synthesis of the optically active S-hydroxy-y-keto a, 3-unsaturated acid fragment 442 via the direct addition of a fra/i.s-vinylogous ester anion equivalent to a readily available Weinreb amide, and the facile construction of the 16-membered macrolide core of the macrosphelide series via an INOC. 

Dipolar cycloaddition reactions between nitrile oxides and aUcenes produce 2-isoxazolines. Through reductive cleavage of the N—O bond of the 2-isoxazohnes, the resulting heterocycles can be readily transformed into a variety of important synthetic intermediates such as p-hydroxy ketones (aldols), p-hydroxy esters, a,p-unsaturated carbonyl compounds, y-amino alcohols, imino ketones and so forth (7-12). 

The hydrolysis of hydroxy, amino or unsaturated esters is usually accompanied by side reactions, loss of chirality or isomerization. Various esters have been selectively hydrolysed at room temperature and in high yields under high pressure in the presence of V-methylmorpholine or Pr2NEt. For example, the hydrolysis of the p,Y-unsaturated diester 105 into p-hydroxyester 106 occurred chemoselectively in 100% yield at high pressure in methanol solution subsequent high-pressure induced hydrolysis of 106, in CH3CN/H2O (60 1) as medium, afforded the desired hydroxy acid 107 as a single product (Scheme 7.27). The usual aqueous procedures produced a mixture of products. 

Pyrones, which are the ring-oxygen equivalents of pyridones, are simply a- and y-hydroxy-pyrylium salts from which an 0-proton has been removed. There is little to recommend that 2- and 4-pyrones be viewed as aromatic they are perhaps best seen as cyclic unsaturated lactones and cyclic p-oxy-a,P-unsaturated-ketones, respectively, for example 2-pyrones are hydrolysed by alkali, just like simpler esters (lactones). It is instructive that, whereas the pyrones are converted into pyridones by reaction with amines or ammonia, the reverse is not the case - pyridones are not transformed into pyrones by water or hydroxide. Some electrophilic C-substitutions are known for pyrones and benzopyrenes, the oxygen guiding the electrophile ortho or para, however there is a tendency for electrophihe addition to the C-C double bond of the heterocyclic ring, again reflecting their non-aromatic nature. Easy Diels-Alder additions to 2-pyrones are further evidence for diene, rather than aromatic, character. 

Further details of phase-transfer addition of dibromocarbene to a,(3-unsaturated esters and ketones [e.g. (18)] and subsequent reductive monode-bromination with tributyltin hydride (Vol. 7, p. 34) have been publishedJulia reports the use of solid NaOH-Et3NCH2Ph CP for the solid-liquid phase-transfer catalytic generation of dichlorocarbene (addition to a-pinene and limonene). Dichlorocarbene also provides a mild and efficient method for the Beckmann fragmentation of anh-a-hydroxy-ketoximes into aldehydes (or ketones) and nitriles [e.g. 2-exo-hydroxy-3-hydroxyiminobornane into (24 X = CHO, Y = CN)]. Trimethylsilylcyclopropanes are synthesized by adding the... 

Synthesis of Alkenes by Reductive Elimination. The treatment of 2-halo-3-hydroxy esters and amides with samarium iodide leads to the corresponding di- or trisubstituted E)-a,p-unsaturated derivatives in high yields and diastereoselectivities (eqs 39 and 40). The precursors are readily accessible by condensation of the lithium enolate of a-haloesters or amides. If the substrate contains y,i5-unsaturation, the /3,y-unsaturated ester is generated in the process (eq 41). 

The transfer hydrogenation of a-keto- S -unsaturated esters, catalyzed by Ru(p-cymene)(TsDPEN) (TsDPEN monotosylated l,2-diphenylethylene-l,2-dia-mine) with 2-propanol as the hydrogen source, has been developed as an efficient method for the preparation of a-hydroxy-)S, y-unsaturated esters or acids. 

In conclusion, we have found a convenient and practical method for the selective reduction of C=0 bond of a wide spectrum of a-keto-)S, -unsaturated esters with Ru(p-cymene)(TsDPEN) as catalyst. The transition metal catalyzed transfer hydrogenation reaction with good selectivity and high efficiency offers possibilities to provide the optically active a-hydroxy-/l, y-unsaturated esters with chiral catalysts. Table 3.8 gives different substrates that can be reduced with Ru(p-cymene) (TsDPEN) complex in isopropyl alcohol. 

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